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Scientist on the road to developing anti-depressant with fewer side effects

Antidepressant with fewer side effects in development with novel delivery system: nasal spray

Fang Liu says creating a drug with little or no side effects is "my dream and my passion." (Thomas Bollmann, Special to the Star / Thomas Bollmann, Special to the Star)

By Anne BokmaSpecial to the Star

Wed., June 11, 2014

While practising as a pediatrician in China more than 20 years ago, Dr. Fang Liu was frustrated by how often her young patients suffered side effects from the medications they were taking. She promised herself one day she would devote her work to developing a drug treatment that wouldn’t make people ill with adverse effects.

“I wanted to create a drug with little or no side effects,” she says, “that became my dream and my passion.”

Liu, now a senior scientist and head of molecular neuroscience at Centre for Addiction and Mental Health, is on her way to recognizing that dream with the development of a promising new antidepressant nasal spray treatment that may be faster acting and reduce or eliminate typical side effects — such as weight gain, nausea and decreased libido — common with current antidepressant drugs.

Ten years in the making, the treatment, which would be delivered directly to the brain through a squirt or puff of vapour in the nose, still has another 10 to 15 years to go before it could potentially come to market. Currently, Liu is seeking an industry partner to provide funding to initiate clinical trials.

In 2004, Liu discovered a potential new target area to treat depression when she examined the autopsied brains of patients who had suffered major depression. She found the binding between two dopamine receptors in these brains was significantly elevated.

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Working from this discovery, she and her team developed a protein peptide that would disrupt the binding between these receptors in the hope it would have an antidepressant effect.

The peptide represented a whole new approach to treating depression, which has typically relied on medications that primarily block serotonin or norepinephrine transporters. The peptide was tested in rats to compare the effects with existing antidepressants.

“After we administered the peptide,” explains Liu, “we saw a marked improvement in depression-related behaviours. The improvement was equivalent to the improvement on traditional antidepressant medication.”

When administered orally, the peptide treatment was unable to cross the blood-brain barrier in sufficient concentrations and had to be injected into the brain.

Liu sourced a unique nasal delivery system — known as a pressurized olfactory delivery device — from a U.S. medical company. When tested in rats, it was able to effectively deliver the peptide to the brain through the nose. Study results were published recently in the scientific journal Neuropsychopharmacology.

“The study marks the first time a peptide treatment has been delivered through nasal passageways to treat depression,” says Liu, who is also a professor in the University of Toronto’s department of psychiatry. “I see the treatment working for depression in much the same way an inhaler is used for asthma.”

Depression is the most common form of mental illness. Patients on antidepressants often feel as though they are wandering in a pharmaceutical wilderness, as more than 50 per cent of people living with depression do not respond to first-line medication treatment. And 10 to 15 per cent of patients continue to experience depressive symptoms even after trying several different antidepressants.

“There is a high percentage of people who never respond to traditional antidepressant drugs. Since we’ve identified a brand new drug target for treatment, the hope is that patients will respond to this,” says Liu, adding the treatment may also be faster acting than traditional medications, which typically take several weeks to work.

“When one drug doesn’t work, patients switch to another or combine two drugs together, which can result in very significant side effects,” she notes. Liu is hopeful this treatment will have a much lower side effect profile, since it targets a protein complex, rather than a single protein.

“Each protein has multiple functions and when you target a single protein all the pathways become blocked, including functions that control things like weight gain and nausea,” she says. “That’s the downside of [traditional] treatments.”

The peptide treatment and its novel nasal delivery system are creating lots of buzz in the psychiatric community, but Liu cautions that there’s still a long way to go before it comes to market.

“My hope is that that by the time I retire at 65,” says Liu, who is 50, “this will be on the market and will represent a new treatment for depression that has fewer side effects.”

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